7-{8 2-(Cycloalkyleneimino-2yl)thioacetamido{9 cephalosporanic acid

ABSTRACT

The anti-bacterial agents of this invention present the following structural formula:   in which R1 is a member selected from the group consisting of -H, alkyl of 1 to 6 carbon atoms and aryl of 6 to 8 carbon atoms; R2 is a member selected from the group consisting of -H, alkanoyloxy of 2 to 6 carbon atoms,   and when taken the 3-carboxyl group, M is a member selected from the group consisting of -H, an alkali metal and -NH4; m is one of the integers 0-2; N IS ONE OF THE INTEGERS 2-4; AND THE PHARMACEUTICALLY ACCEPTABLE HYDROHALIDE ACID ADDITION SALTS THEREOF.

' United States Patent [191 Wei [ Nov. 4, 1975 [5 7-[2-( CYCLOALKYLENEIMINO- 2-YL)THIOACETAMIDO]CEPHALOSPO- RANIC ACID [75] Inventor: Peter H. L. Wei, Springfield, Pa.

[73] Assignee: American Home Products Corporation, New York, NY.

OTHER PUBLICATIONS Crast, Jr., Chemical Abstracts, Vol. 70, 68,389], (1969).

Primary Examiner-R. Gallagher Assistant Examiner-Diana G. Rivers Attorney, Agent, or Firm-Richard K. Jackson [57] ABSTRACT The anti-bacterial agents of this invention present the following structural formula:

45 XSACHQF 6HC0NH I in which R is a member selected from the group consisting of I-I, alkyl of 1 to 6 carbon atoms and aryl of 6 to 8 carbon atoms; R is a member selected from the group consisting of I-I, alkanoyloxy of 2 to 6 carbon atoms,

N-N -81 [G1, s 4

I and when taken the 3-carboxyl group, -N

M is a member selected from the group consisting of -H, an alkali metal and NH m is one of the integers O2; n is one of the integers 2-4; and

the pharmaceutically acceptable hydrohalide acid addition salts thereof.

5 Claims, No Drawings 7-[2-(CYCLOALKYLENEINIINO-2YL)TI-II- OACETAMIDO1CEPHALOSPORANIC ACID DESCRIPTION OF THE INVENTION In accordance with this invention there is provided anti-bacterial agents of the formula:

CO M

in which R is a member selected from the group consisting of H, alkyl of 1 to 6 carbon atoms and aryl of 6 to 8 carbon atoms; R is a member selected from the group consisting of H, alkanoyloxy of 2 to 6 carbon atoms,

and when taken with the 3-carboxyl group,

M is a member selected from the group consisting of -H, an alkali metal and -NH m is one of the integers 0-2; n is one of the integers 2-4; and the pharmaceutically acceptable hydrohalide acid addition salts thereof.

The term alkyl, as it is used herein, is intended to embrace univalent aliphatic hydrocarbons containing the indicated number of carbon atoms, representative of which are the methyl, ethyl, propyl, i-propyl, butyl, i-butyl, amyl and hexyl radicals, The term aryl is in- CO M CO M

in which the values of R R M, n and m are given above and HX represents the hydrohalide addition salt, the halide being that of the haloalkanoylamido cephalosporanic acid derivative employed as a reactant. Preferably, X is C1 or -Br.

The preferred group of compounds, from the standpoint of availability of reactants, ease of reaction and general production economics, are those of the formula:

in which R is a member selected from the group consisting of H, alkyl of 1 to 6 carbon atoms and phenyl; R is a member selected from the group consisting of H and acetoxy; n is 2, 3 or '4; and X is C1 or -Br. The compounds of this invention are active anti-bacterial agents, effective against gram-positive and gramnegative bacteria and resistant. staphlococcus. The activity of the compounds was established by using the well known, scientifically accepted agar serial dilution testing technique whereby specific bacterial strains are grown for 18 hours in brain heart infusion at 35C. Prior to use, the cultures are diluted lO-l with the infusion. Stock concentrations of the anti-bacterial agent are prepared (2.500 ug per milliliter) in a suitable vehi cle. Two-fold dilutions are made with sterile distilled water appropriately buffered. One milliliter quantities of each dilution are incorporated in 9 milliliter Seed agar in sterile Petri plates. The hardened surface is innoculated with the test bacterium using a Steers replicating device. The plates are incubated for 18 hours at 35C. The least amount of anti-bacterial compound that completely inhibits the test organism is the minimum inhibitory concentration (MIC) expressed in micrograms per milliliter.

Hence, the compounds of this invention are useful in the fields of comparative pharmacology and microbiology and for the control and comparative analysis of bacterial colonies. The compounds are to be used to inhibit the growth of bacteria in the conventional manner and by the known methods of utilizing cephalosporin derivatives.

The following examples illustrate the preparation of representative cephalosporin derivatives of this invention. The compounds produced in the following examples are generally recovered in the hydrohalide addition salt form, frequently with a small amount of solvent, the latter being readily removed by further vacuum stripping of the product. The free bases are readily formed by neutralization of the hydrohalide by conventional techniques. The activity of each exemplified product is presented for those specific bacterial strains against which the compound exemplified was active at or below 250 micrograms per milliliter. The representative nature of the bacterial strains employed to demonstrate anti-bacterial activity are indicative of the broader applicability of the compounds of this invention in the control of bacterail infestations other than those specifically referred to in each of the following examples. The bacteria are named, followed by the specific strain and the concentration in micrograms per milliliter at which 100 percent inhibition occurred. The abbreviations for each bacterium are:

BA SU Bacillus subtilis ST AU Staphylococcus aureus HE SP Herella species NE CA Neisseria catarrhalis EN AE Enterobacter aerogenes ES CO Escherichia coli ES lN Escherichia intermedia SA PA Salmonella paratyphi KL PN Klebsiella pneumoniae BO BR Bordetella bronchiseptica PR VU Proteus vulgaris EXAMPLE I 7-[2-(4,5,6,7-Tetrahydro-3H-azepin-2-ylthio)acetamido]cephalosporin acid.

7-[2-Bromoacetamido]cephalosporanic acid (0.78 gram, 2 millimole) and w-thiocaprolactam (0.26 gram, 2 millimole) were dissolved in acetone and the acetone solution was stirred at room temperature for 4 hours. After filtering off some insoluble material the solution was taken to dryness at a temperature below 30C. The residual solid (1.0 gram) was triturated with diethyl ether and collected.

Elemental Analysis for C H N O S HBr /2(C2H5)2Oi Calcd: C, 42.93; H, 5.22; N, 7.50. Found: C, 43.02; H, 4.71; N, 7.13.

BA so 6633 .244 51 AU 6538P .976 ST AU sMrr1-1 .976 ST AU CHP 3.90 s'r AU 53-180 1.95 NE cA 8193 125 ES C0 9637 62.5 sA PA 1 1737 7.81 KL PN 10031 15.6 B0 BR 4617 313 PR V11 6896 31.3

EXAMPLE II 7- 2-( 3,4,5 ,6-Tetrahy dro-2-pyridylthio )acetamido cephalosporanic acid.

The procedure of Example I was repeated with the exception that w-thiovalerolactam was employed rather than w-thiocaprolactam. The product was recovered as the hydrobromide addition salt.

Elemental Analysis for C H N O S HBr /2(CH CO Calcd: C, 41.34; H, 4.69; N, 7.82. Found: C, 40.55; H, 4.51; N, 7.80.

The procedure of Example I was repeated with the exception that w-thiobutyrolactam was substituted for w-thiocaprolactam. The product was recovered as the hydrobromide salt.

Elemental Analysis for C, H N O S HBr /2(CH CO: Calcd: C, 40.15; H, 4.43; N, 8.03. Found: C, 39.92; H, 4.72; N, 8.18.

BA 6633 .488 ST AU 6538P 1.95 ST AU SMITH 1.95 ST AU CH? 7.81 sr AU 53-180 3.90 NE CA 8193 ES C0 9637' 125 ES IN 65-1 250 SA PA 1 1737 15.6 EN AE 13048 125 R1. PN 10031 62.5 BO BR 4617 313 PR vu 6896 62.5

EXAMPLE IV 7-[2-Phenyl-2-(4,5,6,7-tetrahydro-3H-azepin-2-ylthio)acetamido] cephalosporanic acid.

The procedure of Example I was repeated with the exception that 7-[2-bromo-2-phenylacetamido]cephalosporanic acid was employed in lieu of 7-(2- bromoacetamido)cephalosporanic acid.

Elemental Analysis for C H N O S HBr N, 6.74. Found: C, 49.08; H, 5.25; N, 6.40.

What is claimed is: 1. A compound of the formula:

in which 6 R is a member selected from the group consisting of l-l, phenyl, tolyl, ethylphenyl and dimethyl phenyl; R is a member selected from the group consisting of -H, alkanoyloxy of 2 to 6 carbon atoms and, when taken with the 3-carboxyl group,

M is a member selected from the group consisting of H, an alkali metal and NH n is one of the integers 2, 3 or 4; and the pharmaceutically acceptable hydrohalide acid addition salts thereof.

2. The compound which is 7-[2-(4,5,6-7-tetrahydro- 3H-azepin-2-ylthio)acetamido]cephalosporanic acid and the pharmaceutically acceptable hydrohalide addition salts thereof.

3. The compound of claim 1 which is 7-[2-(3,4,5,6- tetrahydro-Z-pyridylthio )acetamido cephalosporanic acid and the pharmaceutically acceptable hydrohalide addition salts thereof.

4. The compound which is 7-[2-(1-pyrrolin-2ylthio)acetamido]cephalosporanic acid and the pharmaceutically acceptable hydrohalide addition salts thereof.

5. The compound which is 7-[2-phenyl-2-(4,5,6,7- tetrahydro-3H azepin-2-ylthio)acetamido1cephalospranic acid and the pharmaceutically acceptable hydrohalide addition salts thereof. 

1. A COMPOUND OF THE FORMULA:
 2. The compound which is 7-(2-(4,5,6-7-tetrahydro-3H-azepin-2-ylthio)acetamido) cephalosporanic acid and the pharmaceutically acceptable hydrohalide addition salts thereof.
 3. The compound of claim 1 which is 7-(2-(3,4,5,6-tetrahydro-2-pyridylthio)acetamido)cephalosporanic acid and the pharmaceutically acceptable hydrohalide addition salts thereof.
 4. The compound which is 7-(2-(1-pyrrolin-2ylthio)acetamido)cephalosporanic acid and the pharmaceutically acceptable hydrohalide addition salts thereof.
 5. The compound which is 7-(2-phenyl-2-(4,5,6,7-tetrahydro-3H-azepin-2 -ylthio)acetamido)cephalospranic acid and the pharmaceutically acceptable hydrohalide addition salts thereof. 